Multiple myeloma (MM) is a plasma cell derived blood cancer that produces monoclonal immunoglobulins (M-Ig). Detection of minimal residual disease (MRD) is of great importance for MM care. All methods used for MRD detection are based on evaluation of plasma cells obtained from bone marrow (BM) biopsies. These methods are susceptible to failure and do not allow frequent monitoring because of their invasiveness. Detection of MRD in peripheral blood is most ideal but remains an unmet medical challenge. Circulating M-Ig proteins are the hallmark of MM, and their detection by currently available serum-based methods, including serum protein electrophoresis (SPEP) and immunofixation (IFE), is used in diagnosis and follow-up, but not MRD monitoring due to insufficient sensitivity. This problem can be addressed by exploiting variable regions (called idiotypes) of M-Ig proteins, which are tumor-specific and unique to the patient. The ability to monitor the presence and reappearance of the same idiotype in blood after therapy would lead to sensitive MRD detection. This can be enabled by idiotype-targeting aptamers as personalized reagents. Aptamers are single-stranded oligonucleotides that specifically bind to targets, and have been demonstrated to allow sensitive serum-based detection of analytes including immunoglobulins. Through an in vitro process termed systematic evolution of ligands by exponential enrichment (SELEX), aptamers are generated from randomized libraries of oligonucleotides. MRD detection requires generation of aptamers targeting the unique idiotype of the patient. This is impractical with conventional SELEX methods that are labor-intensive and time-consuming, but can be enabled by our innovative microfluidic technology that allows rapid generation of aptamers. Our preliminary microfluidic devices have demonstrated the capability of completing the SELEX process within ~10 hours for successful isolation of immunoglobulin-targeting aptamers. Our long-term objective is to realize a paradigm for sensitive detection MRD in peripheral blood using personalized aptamers targeting patient- and tumor-specific idiotypes of M-Ig proteins of individual MM patients. The goal of this project is to validate the ability of our microfluidic technology to rapidly generate idiotype- targeting aptamers for individual patients for sensitive MRD detection in peripheral blood. We will first optimize a SELEX protocol using readily available IgG1/kappa monoclonal antibodies, and then use this protocol to validate microfluidic isolation of aptamers targeting patient M-Ig proteins for serum-based M-Ig detection. At the end of the three-year grant period, we would be ready to initiate a clinical study, including longitudinal, real-time monitoring of actual patients with intact immunoglobulin multiple myeloma (IIMM) with increased levels of the IgG1/kappa monoclonal antibody, while in parallel we will expand and generalize our procedure to other classes/subclasses, enabling personalized reagents capable of dramatically improving MRD detection for optimal care for nearly all MM patients.